DESCRIPTION (Applicant's Description): The Physician Scientist Award (PSA) will provide the opportunity to obtain comprehensive training and experience in biomedical research. It contains a program of both didactic study and basic laboratory research, further defining the molecular basis of the control of cell growth, in the laboratory of Dr. Robert Weinberg at the Whitehead Institute for Biomedical Research. The broad long term objectives of this award are to provide experience in cell biology and biochemistry techniques, to teach how to think creatively, critically and analytically about a research problem, and to lead to the development of skills required for an independent scientific research program. The first part (phase I) of the proposal describes a comprehensive course of didactic study, including attending classes, lectures, and seminars, and participating in floor meetings, lab meetings, and poster sessions. The progress of the candidate will be monitored by a scientific review committee of four professors from the Dana-Farber Cancer Institute, and by the research mentor, Dr. Weinberg. The research plan (phase II) proposes to elucidate further the control of cell growth, by studying the molecular basis of the restriction point. It is at this point where a cell decides whether to commit to DNA replication and cell division. Current research suggests that this decision is determined by hyperphosphorylation of the retinoblastoma protein (pRB), but the precise molecular mechanisms by which this occurs remain unclear. Herein a model is proposed whereby the G1 cyclins (cyclin E and D-type cyclins) and their cognate cyclin-dependent kinases cooperate in hyperphosphorylation of pRB. The model provides a number of specific testable hypotheses regarding pRB phosphorylation. The specific aims of the research are to examine pRB phosphorylation in detail, and to prove the model by testing these hypotheses. To achieve these aims, pRB phosphorylation will be reconstructed in vitro with biochemically pure reagents, and the events that lead to pRB phosphorylation in vivo will be dissected in growing cells. The proposed research addresses an event central to cell replication and proliferation. A more complete understanding of the molecular basis of the restriction point will provide additional insight into the physiology of normal and cancerous cells, and may ultimately translate into more successful or novel therapies for cancer.